Circulating tumor DNA, cancer cells, and exosomes in blood samples demonstrate enhanced sensitivity over traditional cytology for detecting gallbladder malignancies, according to a comprehensive review spanning three decades of research. The approach addresses a critical diagnostic gap since gallbladder anatomy severely limits tissue biopsy access, contributing to the cancer's notorious late-stage detection and poor survival outcomes. This liquid biopsy advancement represents a significant shift in oncological screening paradigms, particularly for cancers in anatomically challenging locations. The technology's ability to capture real-time genetic mutations and tumor heterogeneity offers substantial advantages over static tissue samples, which often miss the dynamic nature of cancer evolution. Early detection capabilities could dramatically improve patient outcomes for gallbladder cancer, which typically presents symptomatically only in advanced stages. However, the review acknowledges variable results across studies and technical challenges that remain unresolved. The clinical translation requires standardized protocols and larger validation cohorts before widespread implementation. While promising, this remains an emerging field requiring further refinement to achieve the precision oncology potential suggested by preliminary findings.